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Relevance to Autism

Several studies have found rare single gene variations in the CNTN4 gene in patients with ASD. These variations include deletions, missense mutations and a duplication. For example, a deletion in the CNTN4 gene was found in a patient with PDD-NOS and mild intellectual disability (Leblond et al., 2012). On the contrary, one study attempted to find a genetic association between CNTN4 variants and autism in a sample of CORA families but did not find any statistically significant results.

Molecular Function

This gene encodes a member of the contactin family of immunoglobulins. Contactins are axon-associated cell adhesion molecules that function in neuronal network formation and plasticity. The encoded protein is a glycosylphosphatidylinositol-anchored neuronal membrane protein that may play a role in the formation of axon connections in the developing nervous system.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Disruption of contactin 4 in three subjects with autism spectrum disorder.
ASD
Positive Association
A candidate gene association study further corroborates involvement of contactin genes in autism.
ASD
Positive Association
Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.
ASD
Positive Association
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
Positive Association
Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.
ASD
Negative Association
No evidence for association of autism with rare heterozygous point mutations in Contactin-Associated Protein-Like 2 (CNTNAP2), or in Other Contacti...
ASD
Support
Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior
Support
Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.
ASD
ID
Support
Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder
ASD
Support
Contactin 4 as an autism susceptibility locus.
ASD
Support
Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with develop...
ID
Behavioral abnormalities
Support
Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder.
ASD
Support
Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.
ASD
Support
Integrating de novo and inherited variants in 42
ASD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Mutational Landscape of Autism Spectrum Disorder Brain Tissue
ASD
Support
Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.
ASD
ID
Support
The autism risk gene CNTN4 modulates dendritic spine formation
ASD
Support
A discovery resource of rare copy number variations in individuals with autism spectrum disorder.
ASD
Highly Cited
Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the i...
Highly Cited
Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.
ASD
DD, ID
Recent Recommendation
Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder.
Recent Recommendation
Human-specific histone methylation signatures at transcription start sites in prefrontal neurons.
Recent Recommendation
The protein tyrosine phosphatases PTPRZ and PTPRG bind to distinct members of the contactin family of neural recognition molecules.
Recent Recommendation
Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome.
Recent Recommendation
BIG-2 mediates olfactory axon convergence to target glomeruli.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN050R001 
 copy_number_loss 
  
  
 Familial 
 Paternal 
 Multiplex 
 GEN050R002 
 copy_number_gain 
  
  
 Familial 
 Paternal 
 Simplex 
 GEN050R003 
 copy_number_loss 
  
  
  
  
 Multiplex 
 GEN050R004 
 copy_number_gain 
  
  
  
  
 Multiplex 
 GEN050R005 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Multiplex 
 GEN050R006 
 missense_variant 
 c.532A>G 
 p.Asn178Asp 
 Familial 
 Maternal 
  
 GEN050R007 
 missense_variant 
 c.662G>A 
 p.Gly221Asp 
 Familial 
 Maternal 
  
 GEN050R008 
 missense_variant 
 c.992A>G 
 p.Glu331Gly 
 Familial 
 Paternal 
  
 GEN050R009 
 missense_variant 
 c.1889A>G 
 p.Tyr630Cys 
 Familial 
 Paternal 
  
 GEN050R010 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN050R011 
 copy_number_loss 
  
  
 Familial 
  
 Multiplex 
 GEN050R012 
 copy_number_gain 
  
  
 Unknown 
  
 Unknown 
 GEN050R013 
 copy_number_loss 
  
  
 Unknown 
  
 Simplex 
 GEN050R014 
 translocation 
  
  
 De novo 
  
  
 GEN050R015 
 missense_variant 
 c.1814T>C 
 p.Ile605Thr 
 De novo 
  
 Simplex 
 GEN050R016 
 splice_site_variant 
 c.1942+2T>C 
  
 Familial 
 Paternal 
  
 GEN050R017 
 complex_structural_alteration 
  
  
 De novo 
  
  
 GEN050R018a 
 copy_number_loss 
  
  
 Familial 
 Both parents 
  
 GEN050R019 
 synonymous_variant 
 c.324A>G 
 p.Thr108%3D 
 Unknown 
  
  
 GEN050R020 
 synonymous_variant 
 c.1278C>T 
 p.Val426%3D 
 De novo 
  
  
 GEN050R021 
 missense_variant 
 c.2542G>C 
 p.Glu848Gln 
 De novo 
  
  
 GEN050R022 
 synonymous_variant 
 c.504T>C 
 p.Asn168%3D 
 De novo 
  
  
 GEN050R023 
 synonymous_variant 
 c.1398C>T 
 p.Asn466%3D 
 De novo 
  
  
 GEN050R024 
 missense_variant 
 c.2128G>A 
 p.Gly710Arg 
 De novo 
  
  
 GEN050R025 
 frameshift_variant 
 c.1860del 
 p.Pro621LeufsTer44 
 Familial 
 Maternal 
 Multiplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN050C001 
 intron_variant 
 rs7641285 
 c.-145+105534C>T;c.-145+38822C>T 
 Allele 1, G; allele 2, A 
 67 ASD patients and 117 healthy controls 
 Discovery 
 GEN050C002 
 intron_variant 
 rs908487 
 c.56-9357T>C 
 A/G 
 67 ASD patients and 117 healthy controls 
 Discovery 
 GEN050C003 
 intron_variant 
 rs17008493 
 c.-145+55783T>A;c.-145+57444T>A;c.-145+56773T>A;c.-145+56792T>A 
  
 166 Japanese ASD probands, 642 healthy Japanese controls 
 Discovery 
 GEN050C004 
 intron_variant 
 rs35346733 
 c.-88-91778G>A 
  
 40,675 SCZ cases and 64,643 controls (CLOZUK and independent PGC datasets) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion-Duplication
 17
 
3
N/A
 2
 
3
Deletion-Duplication
 63
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 2
 
3
Deletion
 3
 
3
Deletion
 4
 
3
Duplication
 14
 
3
Duplication
 1
 

Model Summary

Cntn4 is one of the axon guidance molecules crucial for the formation and maintenance of functional odor map in the olfactory bulb.

References

Type
Title
Author, Year
Primary
BIG-2 mediates olfactory axon convergence to target glomeruli.
Additional
Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models.
Additional
Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior

M_CNTN4_1_KI_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: A floxed neo cassette and transcription/translation stop signal (stop) inserted at a start codon (ATG) in the exon 2 of cntn4 gene.
Allele Type: Targeted (knock-out)
Strain of Origin: 129S/SvEv
Genetic Background: 129S/SvEv * C57BL/6
ES Cell Line: Not Specified
Mutant ES Cell Line: Not Specified
Model Source: Not Specified

M_CNTN4_2_KI_HM

Model Type: Genetic LOF
Model Genotype: Homozygous
Mutation: A floxed neo cassette and transcription/translation stop signal (stop) inserted at a start codon (atg) in the exon 2 of cntn4 gene. (existing construct)
Allele Type: Knockout
Strain of Origin: 129S/SvEv
Genetic Background: C57Bl6/J
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Yoshihiro Yoshihara (RIKEN, Japan), 18367085

M_CNTN4_3_KI_HT

Model Type: Genetic LOF
Model Genotype: Heterozygous
Mutation: A floxed neo cassette and transcription/translation stop signal (stop) inserted at a start codon (atg) in the exon 2 of cntn4 gene.(existing construct)
Allele Type: Knockout
Strain of Origin: 129S/SvEv
Genetic Background: C57Bl6/J
ES Cell Line: NA
Mutant ES Cell Line: NA
Model Source: Yoshihiro Yoshihara (RIKEN, Japan), 18367085

M_CNTN4_1_KI_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Neuroreceptor levels: gaba-r: gabaa2
Decreased
Description: Mutants show reduced cell surface gabaara1 levels in the hippocampus andthalamus and a trend for reduced cell surface gabaara1 levelsin the cortex.
Exp Paradigm: NA
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: nmda receptors2
Decreased
Description: Mutants show reduced cell surface glutamate receptor levels in the cortex and hippocampus compared to controls. mutants show reduced cell surface expression levels of glun1 in the cortex.
Exp Paradigm: NA
 Western blot
 3-6 months
Anatomical projections and connectivity1
Decreased
Description: Ectopic glomerular targeting of olfactory sensory neuron axons
Exp Paradigm: Immunohistochemistry
 Immunohistochemistry
 6- 8 weeks
Neuroreceptor levels: glutamate receptors: ampa receptors2
Decreased
Description: Mutants show reduced cell surface glutamate receptor levels in the cortex and hippocampus compared to controls. mutants show reduced cell surface expression levels of glua2 in the cortex. mutants show reduced cell surface expression levels of glua2 and mg
Exp Paradigm: NA
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: ampa receptors2
Increased
Description: Mutants show increased cell surface glutamate receptor levels in the striatum. mutants show increased cell surface expression levels of glua2 and glua1 in the striatum.
Exp Paradigm: NA
 Western blot
 3-6 months
General characteristics1
 No change
 General observations
 Unreported
Neuroreceptor levels: gaba-r: gabaa2
 No change
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: ampa receptors2
 No change
 Western blot
 3-6 months
Neuroreceptor levels: glutamate receptors: nmda receptors2
 No change
 Western blot
 3-6 months
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neurophysiology, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

M_CNTN4_2_KI_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Dendritic architecture: spine density1
Decreased
Description: Decreased spine number in pyramidal neurons in the ca1 region of the hippocampus
 Golgi-Cox staining
 Adult
Basal dendritic length1
Decreased
Description: Ca1 basal dendrites have significantly reduced total neurite length; no change in total neurite length in granule cell morphology in the dg
 Golgi-Cox staining
 Adult
Neuronal number1
Increased
Description: Increase in number of cells in the dentate gyrus but not hippocampus
 Immunohistochemistry
 8-12 weeks
Dendritic architecture: dendritic tree complexity1
Increased
Description: More sholl apical dendrite intersections
 Sholl analysis
 Adult
Hippocampal morphology1
Increased
Description: Increased area of ca1 and ca3 but not dg
 Histology
 Adult
Dendritic architecture: dendritic thickness1
Increased
Description: Increased apical and basal dendrite volume and surface area in pyramidal neurons in ca1
 Golgi-Cox staining
 Adult
Dendritic architecture: spine morphology1
Decreased
Description: Reduction in the number of mushroom spines in the proximal part of the apical dendrite in pyramidal neurons of the ca1 hippocampus region
 Golgi-Cox staining
 Adult
Circulating corticosterone levels1
Increased
Description: Increased corticosterone levels
 Measurement of enzyme activity
 Adult
Synaptic plasticity: post-tetanic potentiation (PTP)1
Decreased
Description: Decreased hippocampal post tetanic potentiation at 10hz but not 100hz
 Whole-cell patch clamp
 8-12 weeks
Synaptic plasticity: hippocampal LTP1
Decreased
Description: Decreased hippocampal ltp
 Whole-cell patch clamp
 8-12 weeks
Self grooming: artificial stress evoked1
Increased
Description: Increased grooming instead of freezing when exposed to cue
 Fear conditioning test
 Adult
Head scanning1
Increased
Description: No change in small head movements (scanning) when placed in a novel context; increased scanning when exposed to cue
 Fear conditioning test
 Adult
Exploratory activity1
Decreased
Description: Decrease in time spent exploring novel context; no change in time spent exploring when exposed to a cue
 Novel cage test
 Adult
Cued or contextual fear conditioning: Memory of cue1
Decreased
Description: Decreased freezing when exposed to different context and a cue
 Fear conditioning test
 Adult
Cued or contextual fear conditioning: Memory of context1
Increased
Description: Increased contextual freezing time
 Fear conditioning test
 Adult
General characteristics1
 No change
 General observations
 8-12 weeks
Size/growth1
 No change
 Body weight measurement
 8-12 weeks
Object recognition memory1
 No change
 Novel object exploration test
 Adult
Olfactory learning and memory1
 No change
 Buried food test
 Adult
Spatial learning1
 No change
 Object-place recognition test
 Adult
Targeted expression1
 No change
 Western blot
 8-12 weeks
Rearing behavior1
 No change
 Novel cage test
 Adult
Brain size1
 No change
 Measurement of tissue volume
 8-12 weeks
Brain size1
 No change
 Measurement of tissue weight
 8-12 weeks
Hippocampal morphology1
 No change
 Immunohistochemistry
 Adult
Action potential property: threshold1
 No change
 Whole-cell patch clamp
 8-12 weeks
EPSP-spike relationship1
 No change
 Whole-cell patch clamp
 8-12 weeks
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 8-12 weeks
Vertical jumping or back flipping1
 No change
 Novel cage test
 Adult
 Not Reported:

M_CNTN4_3_KI_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Dendritic architecture: dendritic tree complexity1
Increased
Description: No change in sholl apical dendrite intersections; increased basal dendrite intersections
 Sholl analysis
 Adult
Hippocampal morphology1
Increased
Description: Increased area of ca1 and ca3 but not dg
 Histology
 Adult
Circulating corticosterone levels1
Increased
Description: Increased corticosterone levels
 Measurement of enzyme activity
 Adult
Dendritic architecture: spine morphology1
Decreased
Description: Reduction in the number of mushroom spines in the proximal part of the apical dendrite in pyramidal neurons of the ca1 hippocampus region
 Golgi-Cox staining
 Adult
Dendritic architecture: spine density1
Decreased
Description: Decreased spine number in pyramidal neurons in the ca1 region of the hippocampus
 Golgi-Cox staining
 Adult
Synaptic plasticity: hippocampal LTP1
Decreased
Description: Decreased hippocampal ltp
 Whole-cell patch clamp
 8-12 weeks
Synaptic plasticity: post-tetanic potentiation (PTP)1
Decreased
Description: Decreased hippocampal post tetanic potentiation at 10hz but not 100hz
 Whole-cell patch clamp
 8-12 weeks
Self grooming: artificial stress evoked1
Increased
Description: Increased grooming instead of freezing when exposed to cue
 Fear conditioning test
 Adult
Head scanning1
Increased
Description: No change in small head movements (scanning) when placed in a novel context; increased scanning when exposed to cue
 Fear conditioning test
 Adult
Cued or contextual fear conditioning: Memory of context1
Increased
Description: Increased contextual freezing time
 Fear conditioning test
 Adult
Cued or contextual fear conditioning: Memory of cue1
Decreased
Description: Decreased freezing when exposed to different context and a cue
 Fear conditioning test
 Adult
General characteristics1
 No change
 General observations
 8-12 weeks
Size/growth1
 No change
 Body weight measurement
 8-12 weeks
Exploratory activity1
 No change
 Novel cage test
 Adult
Object recognition memory1
 No change
 Novel object exploration test
 Adult
Olfactory learning and memory1
 No change
 Buried food test
 Adult
Spatial learning1
 No change
 Object-place recognition test
 Adult
Rearing behavior1
 No change
 Novel cage test
 Adult
Basal dendritic length1
 No change
 Golgi-Cox staining
 Adult
Brain size1
 No change
 Measurement of tissue volume
 8-12 weeks
Brain size1
 No change
 Measurement of tissue weight
 8-12 weeks
Dendritic architecture: dendritic thickness1
 No change
 Golgi-Cox staining
 Adult
Hippocampal morphology1
 No change
 Immunohistochemistry
 Adult
Action potential property: threshold1
 No change
 Whole-cell patch clamp
 8-12 weeks
EPSP-spike relationship1
 No change
 Whole-cell patch clamp
 8-12 weeks
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 8-12 weeks
Vertical jumping or back flipping1
 No change
 Novel cage test
 Adult
 Not Reported:





Download CNTN4's Cytoscape file

Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
AMY1A amylase, alpha 1A (salivary) 276 Q6NSB3 Y2H; IP; MS; IP/WB
Ishizaki R , et al. 2006
FMR1 fragile X mental retardation 1 2332 G8JLE9 PAR-CLIP
Ascano M Jr , et al. 2012
PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta 5577 P31323 IP/WB
Islam A , et al. 2008
Auts2 autism susceptibility candidate 2 319974 Q6PED7 ChIP-Seq
Oksenberg N , et al. 2014
Ptprg protein tyrosine phosphatase, receptor type, G 19270 Q05909 Affinity chromatography
Bouyain S and Watkins DJ 2010
Zbtb20 zinc finger and BTB domain containing 20 56490 Q8K0L9 ChIP-Seq; Gene microarray
Rasmussen MB , et al. 2014

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